Diabetes insipidus: causes, symptoms and treatment

Diabetes insipidus: causes, symptoms and treatment

Diabetes insipidus is a condition where the body loses too much fluid through urination, causing a significant risk of dangerous dehydration as well as a range of illnesses and conditions. There are two forms of the disease: nephrogenic diabetes insipidus and central diabetes insipidus (also known as neurogenic diabetes insipidus).

A number of factors have been linked to the development of diabetes insipidus, which may also occur in pregnancy or with the use of certain medications. Establishing the cause of the problem can help determine the most appropriate treatment to support the regulation of water balance in the body.

Diabetes insipidus is a condition that can be managed successfully.

What is diabetes insipidus?

An uncommon condition, diabetes insipidus is a disorder affecting the regulation of body fluid levels. Two key symptoms resemble those of the more common forms of diabetes that affect blood sugar levels (diabetes mellitus types 1 and 2).1-5

People with diabetes insipidus produce excessive amounts of urine (polyuria), resulting in frequent urination and, in turn, thirst (polydipsia). However, the underlying cause of these two symptoms is quite different from the causes in types 1 and 2 diabetes.

In diabetes mellitus, elevated blood sugar prompts the production of large volumes of urine to help remove the excess sugar from the body. In diabetes insipidus, it is the body's water balance system itself that is not working properly.

Here are some key points about diabetes insipidus. More detail and supporting information is in the body of this article.

  • Diabetes insipidus is a condition where the body fails to properly control water balance, resulting in excessive urination.
  • Diabetes insipidus can be caused by low or absent secretion of the water-balance hormone vasopressin from the pituitary gland of the brain, or by a poor kidney response to this chemical messenger, which is also called antidiuretic hormone.
  • Excessive production of dilute urine in diabetes insipidus is often accompanied by increased thirst and high water intake.
  • Diabetes insipidus can result in dangerous dehydration if a person does not increase their water intake (such as when a patient cannot communicate their thirst or help themselves).
  • Some other medical conditions resemble diabetes insipidus in terms of high urinary output and excessive thirst. However, polyuria seen in diabetes mellitus types 1 and 2 is a reaction to elevated blood sugar, rather than a condition in itself.
  • Some diuretic drugs and dietary supplements can cause similar symptoms to diabetes insipidus.
  • As diabetes insipidus is not a common condition, diagnosis involves the exclusion of other common possible explanations for symptoms. Where there remains a strong suspicions of true diabetes insipidus, a water deprivation test may be carried out by specialists.
  • The water deprivation test must be done in the safety of close medical supervision because of the risks of dehydration. It is highly reliable in making a firm diagnosis and can distinguish central DI from nephrogenic DI.
  • Treatment depends on the type of diabetes insipidus.
  • If the cause is central (low or absent hormone secretion), hormone replacement is achieved with the drug desmopressin. In mild cases, increasing water intake can be sufficient treatment.
  • If the cause is nephrogenic (renal disease, in which the kidneys fail to respond to the hormone sufficiently), then treatment is aimed at the kidney condition.

What causes diabetes insipidus?

There are two forms of diabetes insipidus, each having a different causal mechanism, despite both being related to a hormone called vasopressin (also called antidiuretic hormone, ADH):2,3

The need to urinate in large volumes can wake people with diabetes insipidus.

  • Central (neurogenic or vasopressin-sensitive) diabetes insipidus: a total or partial lack of vasopressin production - the brain's pituitary gland fails to secrete the hormone
  • Nephrogenic diabetes insipidus: vasopressin secretion is normal, but there is a disordered response to the hormone from the kidneys.

The main symptom, polyuria - excessive urine output - can have other causes, but these would usually be ruled out before making a diagnosis of diabetes insipidus.

For example, undiagnosed or poorly managed diabetes mellitus can cause frequent urination.

In diabetes insipidus, polyuria leads to excessive thirst (polydipsia). In other conditions, excessive intake of water caused by primary polydipsia can lead to polyuria.

Examples of primary polydipsia include a disorder of thirst caused by lesions in the hypothalamus of the brain, which can also be the cause of "adipsic" diabetes insipidus, and a psychological habit of drinking too much water (psychogenic polydipsia).6

Central diabetes insipidus

Central diabetes insipidus - caused by a lowered or absent secretion of vasopressin - can be primary or secondary.3

The cause of primary central DI is often unknown (idiopathic), while other causes result from an abnormality in the gene responsible for vasopressin.

Secondary central DI is an acquired form of the condition brought on by diseases that adversely affect vasopressin secretion. For example, various brain lesions resulting from head injuries, cancers or brain surgery can cause secondary central DI. Other body-wide (systemic) conditions and infections can also bring on central diabetes insipidus.

Nephrogenic diabetes insipidus

Just as with central diabetes insipidus, nephrogenic DI can also be primary - inherited - or secondary - acquired. Nephrogenic causes affect the kidneys' response to vasopressin.2

The inherited form of nephrogenic diabetes insipidus can affect people of all genders and is a result of mutations in the AVPR2 gene in 90% of cases. In rare cases, around 10%, the inherited form of nephrogenic DI results from mutations in the aquaporin-2 (AQP2) gene.13 In a recent study, researchers reported the discovery of 10 novel mutations associated with nephrogenic DI.13

Depending on the form of the genes a person has inherited, the condition results in either complete or partial unresponsiveness of the kidneys to vasopressin, thereby affecting water balance to varying degrees.

The acquired form of nephrogenic diabetes insipidus also reduces the kidneys' ability to concentrate urine when water needs to be conserved. Secondary nephrogenic DI can have numerous causes, including:2

  • Kidney cysts that have developed due to any one of a number of conditions, such as autosomal dominant polycystic kidney disease (ADPKD), nephronophthisis, medullary cystic disease complex, and medullary sponge kidney
  • The release of an obstruction of the outlet tube (ureter) from a kidney (release of obstructing periureteral fibrosis)
  • Kidney infection (pyelonephritis)
  • High blood calcium levels (hypercalcemia)
  • Some types of cancer
  • Numerous drugs, especially lithium, but also demeclocycline, amphotericin B, dexamethasone, dopamine, ifosfamide, ofloxacin, orlistat, and others
  • Rare conditions, such as: amyloidosis - which causes protein deposits in organs, including the kidneys; Sjögren's syndrome - an autoimmune disorder; and Bardet-Biedl syndrome (rare in North America and Europe) - causing kidney failure
  • Chronic hypokalemic nephropathy - kidney disease caused by low blood potassium levels - is a possible cause
  • Cardiopulmonary bypass - which can transiently affect vasopressin levels and may require treatment with desmopressin.15

Recent research has also found that altered function of prostaglandin E2 (PGE2) receptor EP4 may be involved in both inherited and acquired nephrogenic DI. EP4 has been seen to alter the behavior of APQ2, making it a possible therapeutic target for treatment of nephrogenic diabetes insipidus.14

Gestational diabetes insipidus

In rare cases, pregnancy can cause a disturbance of vasopressin (antidiuretic hormone). This is due to the placenta (the organ providing sustenance to the fetus) releasing an enzyme that degrades vasopressin.5-7 This effect peaks during the third trimester of pregnancy.7

Pregnancy also causes a lower thirst threshold in women, stimulating them to drink more fluids, while other normal physiological changes during pregnancy also affect the kidneys' response to the fluid balance hormone vasopressin.7

Gestational diabetes insipidus, which affects only a few cases in every 100,000 pregnancies, is treatable during gestation and resolves two or three weeks following childbirth.6,7

Drugs that affect water balance

Diuretic drugs - commonly referred to as water pills (used in people, for example, with heart failure or peripheral edema, swelling) - can also cause increased urine output.7

Intravenous fluid administration can also be a cause of fluid imbalance, in which case the rate of the drip is stopped or slowed and the polyuria resolves. High-protein tube feeds may also increase urine output.7

Signs and symptoms of diabetes insipidus

  • The main symptom of all cases of diabetes insipidus is polyuria - frequently needing to pass high volumes of dilute urine.1-5
  • The second main symptom is polydipsia - excessive thirst that, in this case, results from the loss of water through urine. The thirst prompts the person with diabetes insipidus to drink large volumes of water.

The need to urinate can disturb sleep (nocturia). The volume of urine passed each day can be anywhere between 3 liters and 20 liters, and up to 30 liters in cases of central diabetes insipidus.2,3

Symptoms that are secondary to the excessive urination include dehydration due to the loss of water, especially in children who may not be able to communicate their thirst. Children may become listless and feverish, have vomiting and/or diarrhea, and may show a delay in their growth.2,3

Other vulnerable people unable to help themselves to water, such as people with dementia, are also at risk of dehydration.

Extreme dehydration can lead to hypernatremia, a condition in which, because of low water, the sodium concentration of the serum in the blood gets very high, and the cells of the body are deprived of water.8 Hypernatremia can lead to neurological symptoms such as neuromuscular excitability, confusion, seizures, or even coma.2,3

Diagnosis and tests for diabetes insipidus

There is a reliable test to help diagnose diabetes insipidus - the water deprivation test - but it has to be performed by a specialist as it can be dangerous to conduct without proper supervision.

The water deprivation test challenges the body's hormonal and kidney responses to dehydration.

The water deprivation test involves allowing the patient to become increasingly dehydrated while giving blood and urine samples. The drug vasopressin is also given to test the kidneys' ability to conserve water in response to the dehydration.2,9-11

In addition to managing the dangers of dehydration, close supervision also allows psychogenic polydipsia to be definitively ruled out. This condition causes a person to compulsively or habitually drink large volumes of water. Someone with psychogenic polydipsia may try to drink some water during this test despite strict instructions against drinking.

The samples taken during the water deprivation test are assessed to determine the concentration of urine and blood, and to measure levels of electrolytes, particularly sodium, in the blood.

Under normal circumstances, dehydration triggers the secretion of vasopressin from the pituitary gland in the brain, telling the kidneys to conserve water and concentrate the urine (raising its osmolality).

In diabetes insipidus, either insufficient vasopressin is released (central DI), or the kidneys are resistant to the hormone (nephrogenic DI).

The osmolality of the urine relative to that of the blood reveals the degree to which the kidneys have failed to concentrate the urine in response to reduced water content in the blood. The different types of diabetes insipidus result in varying degrees of dysfunction.

The two types of DI are further differentiated if the urine concentration then responds to injection or nasal spray of vasopressin. Improvements in urine concentration demonstrate that the kidneys are responding to the hormone's message to improve water conservation, leading to a diagnosis of central DI.

If there is no response to exogenous vasopressin, nephrogenic DI is likely the cause, given that the kidneys have failed to respond to the hormonal messenger.

Before the water deprivation test is carried out by specialists, investigations are done to rule out other explanations for the high volumes of dilute urine, including tests and questions to identify:

  • Diabetes mellitus - blood sugar levels in types 1 and 2 diabetes affect urine output and thirst
  • Drugs (for example, diuretics) or medical conditions that can affect kidney function
  • Psychogenic polydipsia - this is a psychological problem in which excessive water intake creates the high urine output; it can be associated with psychiatric illness such as schizophrenia.

Treatment and prevention of diabetes insipidus

Diabetes insipidus becomes a serious problem only for people who cannot replace the fluid that is lost in the urine, leading to dehydration. If there is free access to water and other fluids, the condition is manageable and the prognosis is good with ongoing treatment.4

Without treatment, central DI can lead to permanent kidney damage; in nephrogenic DI, serious complications are rare if water intake is sufficient.2,3

If there is a reversible or treatable underlying cause of the high urine output, such as diabetes mellitus or drug use, addressing this should help resolve the problem resembling diabetes insipidus.

For central and pregnancy-related diabetes insipidus, drug treatment can correct the fluid imbalance by replacing the vasopressin hormone. For nephrogenic diabetes insipidus, addressing the problem with the kidneys may treat the problem.2-4

Vasopressin hormone replacement or central diabetes insipidus (and gestational diabetes insipidus) uses a synthetic analog of the hormone called desmopressin.2-4.

The drug is ineffective against renal causes and is available as a nasal spray, injection or tablet. It is taken as needed, with care taken not to overdose as this can lead to excessive water retention and, if severe, hyponatremia and fatal water intoxication (this is rare). The drug is otherwise generally safe when used at appropriate doses, with few adverse effects.5,12

Mild cases of central diabetes insipidus, in which there is only partial loss of vasopressin secretion, may not need hormone replacement and can be managed through increased water intake.5

Kidney disease treatments for renal causes - nephrogenic diabetes insipidus - may involve:2-4

  • Anti-inflammatory medicines such as NSAIDS (nonsteroidal anti-inflammatory drugs)
  • Water pills (diuretics such as amiloride and hydrochlorothiazide, HCTZ) - paradoxically, these drugs normally cause higher urine output and can explain why there is polydipsia in other cases of DI, but their effect is the opposite when used as a treatment for nephrogenic DI
  • Lower dietary intake of sodium (from salt) and additional fluid intake as needed.

Diabetes Insipidus for USMLE Step 1 and USMLE Step 2 (Video Medical And Professional 2020).

Section Issues On Medicine: Medical practice